We have generated and analyzed the effects of muscle-specific inhibition of myostatin signaling in mice made obese by high-fat diet feeding. These results show that myostatin inhibition after obesity has developed does not cause weight loss. We have also analyzed blood glucose and glucose and insulin tolerance after myostatin inhibition in other mouse models of diabetes to determine which types of diabetes might be ameliorated by myostatin inhibition. Increasing muscle hypertrophy in a mouse model of lipodystrophic diabetes prevents the development of hyperglycemia and lipidemia. These results show that myostatin inhibition does not improve glucose metabolism solely by preventing obesity.